We have identified an unusual population of neuronal progenitor cells that appear to regulate their cell cycle differently from other CNS progenitor/stem cells. The unusual progenitor cells migrate along a restricted pathway, the rostral migratory stream (RMS), from the anterior part of the forebrain subventricular zone (SVZa) to the subependymal zone (sez) in the middle of the olfactory bulb, and then migrate radially to become terminally postmitotic neurons of the granule cell and glomerular layers of the olfactory bulb. In contrast to other progenitor cells of the CNS, which become postmitotic before they migrate and differentiate, SVZa-derived cells with a neuronal phenotype migrate and repeatedly undergo division. This proposal will investigate whether the unique proliferative behavior of the SVZa-derived cells is due, in part, to the differential regulation of genes controlling cell cycle exit. In particular, based on our published and preliminary data, we hypothesize that SVZa-derived cells maintain the ability to sequentially express, and then down-regulate cyclin-dependent kinase inhibitors (CKIs), which are usually expressed when a neural precursor cell exits the cell cycle. Since an individual SVZa-derived cell may express more than one CKI as it traverses the RMS, we would like to determine how each CKI is involved, singly or cooperatively, in replicating SVZa-derived cells so that an appropriate number of olfactory bulb interneurons are generated. Preliminary evidence indicates that p19<Ink4d> and p27<Kip1> (abbreviated "p19" and "p27") are major CKIs expressed by SVZa-derived neuronal progenitor cells and postmitotic neurons, and therefore may govern SVZa-derived cells': (1) successive divisions, (2) final exit from the cell cycle, and (3) maintenance of the postmitotic state. The following inter-related Specific Aims will be addressed in rodents, including mice with targeted mutations of CKI genes: (1) Determine the roles of p19 and p27 in cell cycle regulation along the RMS and in the postmitotic intemeurons of the olfactory bulb by defining the spatial-temporal expression pattern of these CKIs. (2) Investigate the roles of the CKIs p19 and p27 in successive divisions of SVZa-derived neuronal progenitor cells as they migrate along the RMS and in their exit from the cell cycle by determining the timing of their expression relative to S phase. (3) Test the hypothesis that p19 regulates proliferation of SVZa-derived neuronal progenitor cells by determining whether p19 expression is dynamically regulated. (4) Test the hypothesis that p19 and p27, singly or cooperatively, regulate the cell cycle of SVZa-derived cells in the RMS and/or interneurons of the olfactory bulb by comparing these cells in wild type and genetically altered mice.